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Elucidation of the mechanism for neurodegeneration in prion diseases through neuron-glia cross-talk

Research Project

Project/Area Number 15H02475
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Veterinary medical science
Research InstitutionHokkaido University

Principal Investigator

HOROUICHI MOTOHIRO  北海道大学, 獣医学研究院, 教授 (30219216)

Co-Investigator(Kenkyū-buntansha) 小林 篤史  北海道大学, 獣医学研究院, 准教授 (50431507)
Research Collaborator KURODA minori  
SHAN zhifu  
Project Period (FY) 2015-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥41,210,000 (Direct Cost: ¥31,700,000、Indirect Cost: ¥9,510,000)
Fiscal Year 2018: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
Fiscal Year 2017: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2016: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2015: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000)
Keywordsプリオン / 神経細胞 / ミクログリア / アストロサイト / RNA-seq / AFT3 / 小胞体ストレス応答 / 網羅的遺伝子発現解析 / ERストレス / 獣医学 / 感染症 / 脳神経疾患 / 神経科学 / プリオン病 / RNA-sequencing / 次世代シークエンサー / 自然免疫
Outline of Final Research Achievements

Microglia activation and astrogliosis are observed in the early stage of prion diseases. Therefore, glial activation are thought to be involved in the neurodegeneration, however, details of the mechanisms remain to be elucidated. In this study, first we analyzed the activation state of microgila and astrocyte in prion infected mice by RNA-sequencing. We also analyzed brain regions where neuronal loss was progressively observed in prion-infected mice and analyzed gene expression in the small region. Neuron-enriched genes were selected by bioinformatics and further analyses disclosed that expression of stress-induced transcriptional factor, ATF3, was induced in the lateral dorsal part of the thalamus where progressive neuronal loss was observed. The lateral dorsal part of the thalamus is one of the regions where intense glial activation is observed and thus, it is of interest to elucidate if glial activation induces STF3 induction in prion-infected neurons.

Academic Significance and Societal Importance of the Research Achievements

神経変性疾患におけるグリア細胞の活性化状態の比較解析から、神経変性におけるグリア細胞の役割の理解が一層進むと思われる。本研究におけるミクログリアとアストロサイトの遺伝子発現情報は貴重な基礎データとして活用が期待されるため、独自にデータベース化して公開する方向で検討している。また、転写調節因子ATF3が神経変性機構を理解する鍵となる分子となる可能性があるため、ATF3は今後の重要な研究標的であり、その解析が進むことで、神経変性疾患の新たな治療標的となる可能性もある。

Report

(5 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (39 results)

All 2019 2018 2017 2016 2015 Other

All Int'l Joint Research (5 results) Journal Article (9 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 9 results,  Open Access: 3 results,  Acknowledgement Compliant: 5 results) Presentation (24 results) (of which Int'l Joint Research: 20 results,  Invited: 3 results) Book (1 results)

  • [Int'l Joint Research] Colorado State University(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] National Institute of Health(米国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Daegu Hanny University(韓国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] ロッキー山研究所/国立衛生研究所(米国)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] 国立衛生研究所 ロッキー山研究所(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Estimation of prion infectivity in tissues of cattle infected with atypical BSE by real time-quaking induced conversion assay2019

    • Author(s)
      Sawada K, Suzuki A, Yamasaki T, Iwamaru Y, Matsuura Y, Miyazawa K, Masujin K, Atarashi R, Horiuchi M
    • Journal Title

      Journal of Veterinary Medical Science

      Volume: 81 Issue: 6 Pages: 846-850

    • DOI

      10.1292/jvms.19-0003

    • NAID

      130007660450

    • ISSN
      0916-7250, 1347-7439
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Retrograde transport by clathrin-coated vesicles is involved in intracellular transport of PrPSc in persistently prion-infected cells2018

    • Author(s)
      Yamasaki T, Suzuki A, Hasebe R, Horiuchi M.
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 12241-12241

    • DOI

      10.1038/s41598-018-30775-1

    • NAID

      120006539249

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Flow cytometric detection of PrPSc in neurons and glial cells from prion-infected mouse brains2018

    • Author(s)
      Yamasaki T, Suzuki A, Hasebe R, Horiuchi M.
    • Journal Title

      Journal of Virology

      Volume: 92 Issue: 1

    • DOI

      10.1128/jvi.01457-17

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Therapeutic effect of autologous compact bone-derived mesenchymal stem cell transplantation on prion disease2017

    • Author(s)
      Shan Z, Hirai Y, Nakayama M, Hayashi R, Yamasaki T, Hasebe R, Song CH, Horiuchi M
    • Journal Title

      Journal of General Virology

      Volume: 98 Issue: 10 Pages: 2615-2627

    • DOI

      10.1099/jgv.0.000907

    • NAID

      120006523738

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Comparison of abnormal isoform of prion protein in prion-infected cell lines and primary-cultured neurons by PrPSc-specific immunostaining2016

    • Author(s)
      Tanaka M, Fujiwara A, Suzuki A, Yamasaki T, Hasebe R, Masujin K, Horiuchi M
    • Journal Title

      J Gen Virol

      Volume: 97 Issue: 8 Pages: 030-2042

    • DOI

      10.1099/jgv.0.000514

    • NAID

      120006331855

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] PrPSc-Specific Antibody Reveals C-Terminal Conformational Differences between Prion Strains2016

    • Author(s)
      Saijo E, Hughson AG, Raymond GJ, Suzuki A, Horiuchi M, Caughey B
    • Journal Title

      J Virol

      Volume: 90 Pages: 4905-4913

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Complement factors alter the amount of PrP(Sc) in primary-cultured mouse cortical neurons associated with increased membrane permeability2016

    • Author(s)
      Hasebe R, Tanaka M, Suzuki A, Yamasaki T, Horiuchi M
    • Journal Title

      Virology

      Volume: 496 Pages: 9-20

    • DOI

      10.1016/j.virol.2016.05.014

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Establishment of a simple cell-based ELISA for the direct detection of abnormal isoform of prion protein from prion-infected cells without cell lysis and proteinase K treatment2016

    • Author(s)
      Shan Z, Yamasaki T, Suzuki A, Hasebe R, Horiuchi M
    • Journal Title

      Prion

      Volume: 10 Issue: 4 Pages: 305-318

    • DOI

      10.1080/19336896.2016.1189053

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] PrPSc-Specific Antibody Reveals C-terminal Conformational Differences between Prion Strains2016

    • Author(s)
      Saijo E, Hughson AG, Raymond GJ, Suzuki A, Horiuchi M, Caughey B
    • Journal Title

      J Virol

      Volume: 90 Issue: 10 Pages: 4905-4913

    • DOI

      10.1128/jvi.00088-16

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Alteration of microglial activation state by mesenchymal stem cells2018

    • Author(s)
      Nakayama M, Shan Z, Yamasaki T, Hasebe R, Sawada K, Horiuchi M
    • Organizer
      Prion2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification and transcriptome analysis of brain regions vulnerable to neuronal loss in prion infection2018

    • Author(s)
      Shimakura A, Yamasak T, Hasebe R, Horiuchi M
    • Organizer
      Prion2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The estimation of infectivity titers in tissues of cattle infected with atypical BSE by RT-QuIC2018

    • Author(s)
      Sawada K, Suzuki A, Yamasak T, Hasebe R, Iwamaru Y, Matsuura Y, Miyazawa K, Atarashi R, Horiuchi M
    • Organizer
      Asian Pacific Prion Symposium 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Attempt to establish ex vivo co-culture system for analyses of the mechanism for neurodegeneration in prion diseases2018

    • Author(s)
      Takamine H, Tanaka M, Yamasak T, Hasebe R, Horiuchi M
    • Organizer
      Asian Pacific Prion Symposium 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Direct effects of PrPSc on synaptopathy and transcriptional alterations in cultured neurons2018

    • Author(s)
      Tanaka M, Yamasak T, Hasebe R, Horiuchi M
    • Organizer
      Asian Pacific Prion Symposium 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 神経細胞特異的遺伝子発現解析によるプリオン病の神経変性機構の解析2018

    • Author(s)
      島倉綾乃、山崎剛士、鈴木章夫、長谷部理絵、堀内基広
    • Organizer
      第161回日本獣医学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 緻密骨由来間葉系幹細胞によるミクログリアの活性化状態の調節2018

    • Author(s)
      中山ももこ、Shan Zhifu、澤田 和平、山﨑剛士、長谷部理絵、堀内基広
    • Organizer
      第161回日本獣医学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 定型BSEおよび非定型BSEプリオンに感染したマウスの脳のトランスクリプトーム解析2018

    • Author(s)
      山崎剛士、岩丸祥史、鈴木章夫、長谷部理絵、堀内基広
    • Organizer
      第161回日本獣医学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Comparison of intracerebral spread of abnormal isoform of prion protein between three rodent prion strains2018

    • Author(s)
      Yamasaki T, Suzuki A, Hasebe R, and Horiuchi M
    • Organizer
      第66回日本ウイルス学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Unique reactivity of cervid recombinant PrP for the detection of L-BSE and CWD by RT-QuIC2017

    • Author(s)
      Suzuki A, Yamasaki T, Hasebe R, Horiuchi M
    • Organizer
      Prion2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Therapeutic effect of autologous compact bone-derived mesenchymal stem cell transplantation on prion disease2017

    • Author(s)
      Shan Z, Hirai Y, Hayashi R, Yamasaki T, Hasebe R, Song CH, Horiuchi M
    • Organizer
      Prion2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Analyses of neuron-autonomous mechanisms for neurodegeneration in prion diseases on neuron-enriched primary cell cultures2017

    • Author(s)
      Tanaka M, Yamasaki T, Suzuki A, Hasebe R, Horiuchi M
    • Organizer
      Asian Pacific Prion Symposium 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Characterization of gene expression profiles in brains of mice infected with typical and atypical BSEs2017

    • Author(s)
      Yamasaki T, Iwamaru Y, Matsuura Y, Kuroda M, Hasebe R, Okada H, and Horiuchi M
    • Organizer
      Asian Pacific Prion Symposium 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Activation state of glial cells in prion diseases2017

    • Author(s)
      Kuroda M, Yamasaki T, Hasebe R, Horiuchi M
    • Organizer
      Asian Pacific Prion Symposium 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Activation state of glial cells in prion diseases2017

    • Author(s)
      Kuroda M, Yamasaki T, Hasebe R, Horiuchi M
    • Organizer
      Joint Symposium between Seoul National University-Hokkaido Univerisyt “Infection and Immunity”
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Comparison of abnormal isoform of prion protein (PrPSc) in prion-infected cell lines and primary cultured neurons by PrPSc-specific immunostaining2016

    • Author(s)
      Tanaka M, Fujiwara A, Suzuki A, Yamasaki T, Hasebe R, Masujin K, Horiuchi M
    • Organizer
      Prion2016
    • Place of Presentation
      Hitotsubashi-kaikan, Tokyo, Japan
    • Year and Date
      2016-05-10
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Activation state of glial cells in prion diseases2016

    • Author(s)
      Horiuchi M
    • Organizer
      Prion2016
    • Place of Presentation
      Hitotsubashi-kaikan, Tokyo, Japan
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Neuron and glial cell type-specific detection of PrPSc in prion-infected mouse brain by flow cytometry2016

    • Author(s)
      Yamasaki T, Suzuki A, Hasebe R, Horiuchi M
    • Organizer
      Prion2016
    • Place of Presentation
      Hitotsubashi-kaikan, Tokyo, Japan
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Utility of cervid recombinant PrP for the detection of L-BSE and CDW prions by RT-QuIC2016

    • Author(s)
      Suzuki A, Yamasaki T, Hasebe R, Horiuchi M
    • Organizer
      第64回日本ウイルス学会
    • Place of Presentation
      札幌コンベンションセンター、札幌
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Immuno- and cell therapy as possible treatment for prion diseases2015

    • Author(s)
      Horiuchi M
    • Organizer
      Therapeutic approaches to prion disease and other neurodegenerative conditions associated with protein misfolding
    • Place of Presentation
      Banbury Center, Cold Spring Harbor, USA
    • Year and Date
      2015-09-18
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Comparison of PrPSc-specific staining with two anti-PrP monoclonal antibodies in immuno-cytochemistry2015

    • Author(s)
      Tanaka M, Masujin K, Yamasaki T, Suzuki A, Hasebe R, Horiuchi M
    • Organizer
      APPS2015
    • Place of Presentation
      Kanazawa-Ongakudo, Kanazawa, Japan
    • Year and Date
      2015-09-04
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Analysis of activation state of astrocytes with the progression of prion diseases2015

    • Author(s)
      Kuroda M, Yamasaki T, Suzuki A, Hasebe R, Horiuchi M.
    • Organizer
      Prion2015
    • Place of Presentation
      Colorado State University, Fort Collins, Colorado, USA
    • Year and Date
      2015-05-27
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Highthrouput detection of PrPSc from prion-infected cells without PK treatment: Cell-based ELISA for novel screening method for anti-prion compounds2015

    • Author(s)
      Shan Z, Yamasaki T, Suzuki A, Hasebe R, Horiuchi M
    • Organizer
      Prion2015
    • Place of Presentation
      Colorado State University, Fort Collins, Colorado, USA
    • Year and Date
      2015-05-27
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Flow cytometric detection of PrPSc in neurons from prion-infected mouse brain2015

    • Author(s)
      Yamasaki T, Suzuki A, Hasebe R, Horiuchi M
    • Organizer
      Prion2015
    • Place of Presentation
      Colorado State University, Fort Collins, Colorado, USA
    • Year and Date
      2015-05-27
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Book] 人獣共通感染症改訂3版 「牛海綿状脳症、変異クロイツフェルト・ヤコブ病」の項(pp184-189)を分担執筆2015

    • Author(s)
      堀内 基広
    • Total Pages
      447
    • Publisher
      医薬ジャーナル社
    • Related Report
      2015 Annual Research Report

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Published: 2015-04-16   Modified: 2022-08-22  

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